A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (MK-7962-003/A011-11)(STELLAR)

• ClinicalTrials.gov Identifier: NCT04576988
• Recruitment Status: Completed
• First Posted: October 6, 2020
• Last Update Posted: January 26, 2023
• Sponsor: Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
• Information provided by (Responsible Party): Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

Tracking Information

• First Submitted Date: September 28, 2020
• First Posted Date: October 6, 2020
• Last Update Posted Date: January 26, 2023
• Actual Study Start Date: January 25, 2021
• Actual Primary Completion Date: August 26, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 24, 2023)

Change From Baseline in 6-Minute Walk Distance (6MWD) at Week 24 [ Time Frame: Baseline and Week 24 ]

The 6MWD is the distance walked in 6 minutes as a measure of functional capacity. This will be assessed using the 6-minute walk test (6MWT). The change from baseline in 6MWD at Week 24 will be reported.

• Original Primary Outcome Measures (submitted: October 1, 2020): Change from baseline in 6MWD. [ Time Frame: From initiation of treatment to Week 24 ]

Current Secondary Outcome Measures (submitted: January 24, 2023)

• Change From Baseline in Achieving Multicomponent Improvement Endpoint of 6MWD, N-terminal prohormone Btype natriuretic peptide (NT-ProBNP) and World Health Organization (WHO) Functional Class (FC) at Week 24 [ Time Frame: Baseline and Week 24 ]
  Multicomponent Improvement was defined as consisting of all of the following: (a) Improvement in 6MWD (increase ≥30 meters) (b) Improvement in N-terminal pro b-type natriuretic peptide (NT-proBNP; decrease in NT-proBNP ≥30%) or maintenance/achievement of NT-proBNP level <300 ng/L (c) Improvement in World Health Organization (WHO) Functional Class (FC) or maintenance of WHO FC II. Change from baseline in achieving multicomponent improvement endpoint at Week 24 will be reported.
• Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 24 [ Time Frame: Baseline and Week 24 ]
  PVR is a hemodynamic variable of pulmonary circulation and will be measured by right heart catheterization (RHC). The change from baseline in PVR at Week 24 will be reported.
• Change From Baseline in NT-proBNP Levels at Week 24 [ Time Frame: Baseline and Week 24 ]
  NT-proBNP is a circulating biomarker that reflects myocardial stretch. The change from baseline in NT-proBNP level at Week 24 will be reported.
• Percentage of Participants Who Improve in WHO FC at Week 24 [ Time Frame: Baseline and Week 24 ]
  The severity of participant's pulmonary arterial hypertension (PAH) symptoms will be graded using the WHO FC system. WHO functional classification for PAH ranges from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). The change from baseline in WHO FC will be classified into "Improved", "No change" and "Worsened". Improvement = reduction in FC, worsened = increase in FC and no change = no change in FC.
• Time to Death or the First Occurrence of Clinical Worsening Events [ Time Frame: Up to approximately 18 months ]
  Clinical Worsening events are defined as any of the following: worsening-related listing for lung and/or heart transplant; need to initiate rescue therapy with an approved background PAH therapy or the need to increase the dose of infusion prostacyclin by 10% or more; need for atrial septostomy; hospitalization for worsening of PAH (≥ 24 hours); or deterioration of PAH defined by both of the following events occurring at any time: worsened WHO FC and decrease in 6MWD by ≥15% confirmed by 2 tests at least 4 hours apart, but no more than 1 week. Time to Death or the First Occurrence of Clinical Worsening Events will be reported.
• Change From Baseline in Percentage of Participants Who Maintain or Achieve a Low Risk Score Using the Simplified French Risk Score Calculator at Week 24 [ Time Frame: Baseline and Week 24 ]
  The simplified French risk scoring system is based on the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines for the diagnosis and treatment ofpulmonary hypertension (PH). In this study, the noninvasive parameters will be used to determine the score. 'Low risk' is defined as attaining or maintaining all 3 low-risk criteria: WHO FC I or II, 6MWD > 440 m, and NT-proBNP <300 ng/L. Change from baseline in percentage of participants who maintain or achieve a low risk score using the simplified French risk score calculator at Week 24 will be reported.
• Change From Baseline in the Physical Impacts Domain Score of Pulmonary Arterial Hypertension - Symptoms and Impact (PAH-SYMPACT®) at Week 24 [ Time Frame: Baseline and Week 24 ]
  The PAH SYMPACT is a 23-item questionnaire to measure pulmonary arterial hypertension (PAH)-related symptoms and impact of PAH on daily life. The physical impact domain consists of walking slowly on a flat surface, walking quickly on a flat surface, walking uphill, carrying things, doing light indoor household chores, washing or dressing oneself, and needing help from others. Participants will be asked to recall and report on each item experienced in past 7 days. Score for each item ranges from 0 (not difficult at all) to 4 (extremely difficult). A higher score indicates more severe physical impact. The change from baseline in the physical impacts domain score at Week 24 will be reported.
• Change From Baseline in the Cardiopulmonary Symptoms Domain Score of PAH-SYMPACT® at Week 24 [ Time Frame: Baseline and Week 24 ]
  The PAH SYMPACT is a 23-item questionnaire to measure pulmonary arterial hypertension (PAH)-related symptoms and impact of PAH on daily life. The cardiopulmonary symptoms consist of shortness of breath, fatigue, lack of energy, swelling in the ankles or legs, swelling in the stomach area, and cough. Participants will be asked to recall and report on each item experienced in past 7 days. Score for each item ranges from 0 (no symptom at all) to 4 (very severe symptoms). A higher score indicates more severe symptoms experienced. The change from baseline in the cardiopulmonary domain score at Week 24 will be reported.
• Change From Baseline in the Cognitive/Emotional Impacts Domain Score of PAH-SYMPACT® at Week 24 [ Time Frame: Baseline and Week 24 ]
  The PAH SYMPACT is a 23-item questionnaire to measure pulmonary arterial hypertension (PAH)-related symptoms and impact of PAH on daily life. The Cognitive/Emotional Impact domain consists of thinking clearly, feeling sad, feeling worried, and feeling frustrated. Participants will be asked to recall and report on each item experienced in past 7 days. Score for each item ranges from 0 (not difficult at all) to 4 (extremely difficult). A higher score indicates more severe cognitive/emotional impact. The change from baseline in the cognitive/emotional impacts domain score at Week 24 will be reported.

Original Secondary Outcome Measures (submitted: October 1, 2020)

• The proportion of participants achieving the multicomponent improvement endpoint, consisting of all of the following: [ Time Frame: From initiation of treatment to Week 24 ]
  • Improvement in 6MWD (increase ≥ 30 m)
  • Improvement in NT-proBNP (decrease in NT-proBNP ≥ 30%) or maintenance/achievement of NT-proBNP level < 300 ng/L
  • Improvement in WHO FC or maintenance of WHO FC II
• Change from baseline in pulmonary vascular resistance (PVR). [ Time Frame: From initiation of treatment to Week 24 ]
• Change from baseline in NT-proBNP levels. [ Time Frame: From initiation of treatment to Week 24 ]
• Time to death or the first occurrence of any of the following clinical worsening events (TTCW): [ Time Frame: From initiation of treatment to through study completion, an average of 1 year. ]
  • Worsening-related listing for lung and/or heart transplant
  • Need to initiate rescue therapy with an approved background PAH therapy or the need to increase the dose of infusion prostacyclin by 10% or more
  • Need for atrial septostomy
  • PAH-specific hospitalization (≥ 24 hours)
  • Deterioration of PAH defined by both of the following events occurring at any time, even if they began at different times, as compared to their baseline values:
    • Worsened WHO FC
    • Decrease in 6MWD by ≥ 15% confirmed by 2 tests at least 4 hours apart, but no more than 1 week
• Proportion of participants who maintain or achieve a low risk score using the simplified French Risk score calculator. [ Time Frame: From initiation of treatment to Week 24 ]
• Change from baseline in EuroQol 5 dimension 5 level (EQ-5D-5L) index score. [ Time Frame: From initiation of treatment to Week 24 ]
• Change from baseline in Pulmonary Arterial Hypertension - Symptoms and Impact (PAH-SYMPACT®). [ Time Frame: From initiation of treatment to Week 24 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (MK-7962-003/A011-11)(STELLAR)
• Official Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Compare the Efficacy and Safety of Sotatercept Versus Placebo When Added to Background Pulmonary Arterial Hypertension (PAH) Therapy for the Treatment of PAH
• Brief Summary: The objectives of this study are to evaluate the efficacy and safety of sotatercept (MK-7962) treatment (plus background pulmonary arterial hypertension (PAH) therapy) versus placebo (plus background PAH therapy) at 24 weeks in adults with PAH. The primary hypothesis of the study is that the participants receiving sotatercept will have improved 6-minute walk distance (6MWK) at 24 weeks compared to participants receiving placebo.

Detailed Description

This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, parallel-group study in subjects with symptomatic PAH who present with idiopathic or heritable PAH, PAH associated with connective tissue diseases (CTD), drug or toxin induced, post shunt correction PAH, or PAH presenting at least 1 year following the correction of congenital heart defects (CHDs), and currently on background PAH therapy.

The primary efficacy endpoint of the study is exercise capacity, as measured by the 6-minute walk distance (6MWD) measured at 24 week following initiation of treatment.

Study duration will be approximately 2 years. A stratified Wilcoxon test will be used for analysis of the primary endpoint, with appropriate imputation for missing data, as detailed in the Statistical Analysis Plan. An unblinded, external, independent Data Monitoring Committee (DMC) will monitor participant safety throughout the course of the study. Participants completing this study will be eligible to receive sotatercept in a separate, open-label extension study.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Participants will be randomized to one of two treatment arms to receive either sotatercept (0.7 mg/kg) by subcutaneous administration once every 3 weeks, or placebo. All participants will be on concurrent, stable background PAH therapy. Randomization will be stratified by baseline WHO Functional Class (Class II or III) and by background PAH therapy (mono/double or triple therapy)

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Study participants, care providers. Investigators and outcomes assessor will be masked to the study intervention until the final participant completes the 24-week efficacy assessment.

Primary Purpose: Treatment

• Condition: Pulmonary Arterial Hypertension

Intervention

• Biological: Sotatercept
  Sotatercept at a starting dose of 0.3 mg/kg with a target dose of 0.7 mg/kg administered subcutaneously (SC) every 21 days plus background PAH therapy.
  Other Names:

  • MK-7962
  • ACE-011
• Drug: Placebo
  Placebo administered subcutaneously (SC) every 21 days plus background PAH therapy.
• Drug: Background PAH Therapy
  Background PAH therapy refers to combination therapy consisting of drugs from two or more of the following drug classes: an endothelin-receptor antagonist (ERA), a phosphodiesterase 5(PDE5) inhibitor, a soluble guanylate cyclase stimulator, and/or a prostacyclin analogue or receptor agonist.

Study Arms

• Experimental: Sotatercept plus background PAH therapy
  Sotatercept at a starting dose of 0.3 mg/kg with a target dose of 0.7 mg/kg administered subcutaneously (SC) every 21 days plus background PAH therapy
  Interventions:

  • Biological: Sotatercept
  • Drug: Background PAH Therapy
• Placebo Comparator: Placebo plus background PAH therapy
  Placebo administered (SC) every 21 days plus background PAH therapy
  Interventions:

  • Drug: Placebo
  • Drug: Background PAH Therapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 22, 2022): 324
• Original Estimated Enrollment (submitted: October 1, 2020): 284
• Actual Study Completion Date: December 6, 2022
• Actual Primary Completion Date: August 26, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

• Age ≥ 18 years

• Documented diagnostic right heart catheterization (RHC) at any time prior to screening confirming the diagnosis of World Health Organization (WHO) pulmonary arterial hypertension (PAH) Group 1 in any of the following subtypes:

  • Idiopathic PAH
  • Heritable PAH
  • Drug/toxin-induced PAH
  • PAH associated with connective tissue disease
  • PAH associated with simple, congenital systemic to pulmonary shunts at least 1 year following repair
• Symptomatic PAH classified as WHO Functional Class (FC) II or III
• Baseline RHC performed during the Screening Period documenting a minimum pulmonary vascular resistance (PVR) of ≥ 5 Wood units (WU) and a pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure of ≤ 15 mmHg.
• On stable doses of background PAH therapy and diuretics (i.e., patient-specific dose goal for each therapy already achieved) for at least 90 days prior to screening; for infusion prostacyclins, dose adjustment within 10% of optimal dose is allowed per medical practice.
• 6-Minute Walk Distance (6MWD) ≥ 150 and ≤ 500 m repeated twice at screening (measured at least 4 hours apart, but no longer than 1 week), and both values are within 15% of each other (calculated from the highest value)

• Females of childbearing potential must:

  • Have 2 negative urine or serum pregnancy tests as verified by the investigator prior to starting study therapy; she must agree to ongoing urine or serum pregnancy testing during the study and until 8 weeks after the last dose of the study drug
  • If sexually active, have used, and agree to use, highly effective contraception without interruption, for at least 28 days prior to starting the investigational product, during the study (including dose interruptions), and for 16 weeks (112 days) after discontinuation of study treatment
  • Refrain from breastfeeding a child or donating blood, eggs, or ovum for the duration of the study and for at least 16 weeks (112 days) after the last dose of study treatment
  • Male participants must:
  • Agree to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (e.g., polyurethane), during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 16 weeks (112 days) following investigational product discontinuation, even if he has undergone a successful vasectomy
  • Refrain from donating blood or sperm for the duration of the study and for 16 weeks (112 days) after the last dose of study treatment
  • Ability to adhere to study visit schedule and understand and comply with all protocol requirements
  • Ability to understand and provide written informed consent

Key Exclusion Criteria:

• Diagnosis of pulmonary hypertension WHO Groups 2, 3, 4, or 5
• Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus (HIV)-associated PAH and PAH associated with portal hypertension. Exclusions in PAH Group I should also include schistosomiasis associate PAH and pulmonary veno occlusive disease
• Hemoglobin (Hgb) at screening above gender-specific upper limit of normal (ULN), per local laboratory test
• Baseline platelet count < 50,000/mm^3 (< 50.0 x 109/L) at screening
• Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure > 160 mmHg or sitting diastolic blood pressure > 100 mmHg during screening visit after a period of rest
• Baseline systolic blood pressure < 90 mmHg at screening
• Pregnant or breastfeeding women

• Any of the following clinical laboratory values at the screening visit:

  • Estimated glomerular filtration rate (eGFR) < 30 mL/min/m2 (as defined by the Modification of Diet in Renal Disease [MDRD] equation)
  • Serum alanine aminotransferase, aspartate aminotransferase, or total bilirubin levels > 3 × ULN (bilirubin criterion waived if there is a documented history of Gilbert's syndrome)
• Currently enrolled in or have completed any other investigational product study within 30 days for small molecule drugs or within 5 half-lives for biologics prior to the date of signed informed consent
• Prior exposure to sotatercept (ACE-011) or luspatercept (ACE 536) and/or excipients or known allergic reaction to either one
• History of full pneumonectomy
• Pulmonary function test (PFT) values of forced vital capacity (FVC) < 60% predicted at the screening visit or within 6 months prior to the screening visit. If PFT is not available, a chest CT scan showing more than mild interstitial lung disease (ILD) at the screening visit or 1 year prior to it
• Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior to the screening visit or planned initiation during the study (participants who are stable in the maintenance phase of a program and who will continue for the duration of the study are eligible)
• History of more than mild obstructive sleep apnea that is untreated
• Known history of portal hypertension or chronic liver disease, including hepatitis B and/or hepatitis C (with evidence of recent infection and/or active virus replication), defined as mild to severe hepatic impairment (Child-Pugh Class A-C)
• History of restrictive, constrictive or congestive cardiomyopathy
• History of atrial septostomy within 180 days prior to the screening visit
• Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) > 500 ms during the screening period
• Personal or family history of long QT syndrome (LQTS) or sudden cardiac death
• Left ventricular ejection fraction < 45% on historical echocardiogram within 6 months prior to the screening visit
• Any symptomatic coronary disease events (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain) within 6 months prior to the screening visit. Note: Anginal pain can be ignored as an exclusion criterion if coronary angiography shows no obstructions
• Cerebrovascular accident within 3 months prior to the screening visit
• Acutely decompensated heart failure within 30 days prior to the screening visit, as per investigator assessment
• Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease
• Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin) within 30 days prior to the screening visit

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, Brazil, Canada, Czechia, France, Germany, Israel, Italy, Korea, Republic of, Mexico, Netherlands, New Zealand, Poland, Serbia, Spain, Sweden, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT04576988
• Other Study ID Numbers: 7962-003; 7962-003 ( Other Identifier: Merck ); 2020-004142-11 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Current Responsible Party: Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
• Original Responsible Party: Same as current
• Current Study Sponsor: Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
• Verification Date: January 2023